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memo - Magazine of European Medical Oncology

09.02.2024 | original report

β-adrenergic modulation of IL-6/gp130 and SOCS-1 in multiple myeloma: therapeutic strategy for stress induced-inflammatory response

verfasst von: Raika Naiebi, Saeid Abroun, Ph. D., Amir Atashi, Leila Shafiee, Mohammadarian Akbari, Mohammad Hasan Maleki, Morvarid Siri, M. Sc.

Erschienen in: memo - Magazine of European Medical Oncology

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Summary

Purpose

Multiple Myeloma (MM) is considered an incurable, biologically heterogeneous disease of the plasma cells. The clinical data on the association between stress and the molecular mechanism of stress hormone receptor expression and its relationship with IL‑6 signaling pathway have not yet proposed a clear answer in MM. This study aims to explore the effect of isoproterenol and propranolol, which are beta-adrenergic agonists and antagonists, respectively on suppressor of cytokine signaling (SOCS) and IL-6/gp130 signaling in MM cell lines.

Material and methods

Four different MM cell lines (KMM‑1, RPMI 8226, LP‑1, and L363) were treated with isoproterenol and propranolol. Optimal dosages of isoproterenol and propranolol were determined, and the mRNA expression levels of IL‑6, gp130, and SOCS‑1 were examined using qRT-PCR.

Results

The analysis of our results indicated that propranolol, as a β-adrenoreceptor antagonist, could increase MM cell death and ameliorate IL‑6 and its receptor gp130 in addition to up-regulate SOCS‑1 gene expression. On the other hand, isoproterenol, as a β-adrenoreceptor agonist, could provoke MM cell viability and IL‑6 expression.

Conclusions

β‑adrenergic signaling seems to affect cell viability through targeting IL-6/gp130 and SOCS‑1 signaling in MM, underscoring the importance of further studies on stress hormones and IL‑6 suppressors as potent candidates for MM therapy.
Literatur
1.
Bhatt P, Kloock C, Comenzo R. Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse. Curr Oncol. 2023;30(2):2322–47.PubMedPubMedCentralCrossRef
2.
Plakhova N, et al. Mesenchymal stromal cell senescence in haematological malignancies. Cancer Metastasis Rev. 2023;42(1):277–96.PubMedCrossRef
3.
Cippitelli M, et al. Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells. Int J Mol Sci. 2023;24(3).
4.
Harmer D, Falank C, Reagan MR. Interleukin‑6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma. Front Endocrinol (lausanne). 2018;9:788.PubMedCrossRef
5.
Kurzrock R, et al. A phase I, open-label study of siltuximab, an anti-IL‑6 monoclonal antibody, in patients with B‑cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013;19(13):3659–70.PubMedCrossRef
6.
Orlowski RZ, et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL‑6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015;90(1):42–9.PubMedPubMedCentralCrossRef
7.
Tupitsyn N, et al. Functional interaction of the gp80 and gp130 IL‑6 receptors in human B cell malignancies. Clin Lab Haematol. 1998;20(6):345–52.PubMedCrossRef
8.
9.
10.
Galm O, et al. SOCS‑1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood. 2003;101(7):2784–8.PubMedCrossRef
11.
12.
Görgün, G., et al., Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood, The Journal of the American Society of Hematology, 2010. 116(17): p. 3227–3237.
13.
To KF, et al. Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS‑1 in human gastric cancer cell line. Br J Cancer. 2004;91(7):1335–41.PubMedPubMedCentralCrossRef
14.
Beldi-Ferchiou A, et al. Abnormal repression of SHP‑1, SHP‑2 and SOCS‑1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma. PLoS ONE. 2017;12(e0174835):4.
15.
16.
Carey P, et al. Metalloproteinases in Ovarian Cancer. Int J Mol Sci. 2021;22(7).
17.
Yang EV, et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP‑9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66(21):10357–64.PubMedCrossRef
18.
Gornikiewicz A, et al. Catecholamines up-regulate lipopolysaccharide-induced IL‑6 production in human microvascular endothelial cells. Faseb J. 2000;14(9):1093–100.PubMedCrossRef
19.
20.
Szymanski MW, Singh DP. Isoproterenol, in StatPearls. 2023. Statpearls Publ Copyr. 2023;. StatPearls Publishing LLC.: Treasure Island (FL).
21.
Bigley AB, et al. Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Part II: impact of latent cytomegalovirus infection and catecholamine sensitivity. Brain Behav Immun. 2015;49:59–65.PubMedCrossRef
22.
Rodrigues W, et al. Low dose of propranolol down-modulates bone resorption by inhibiting inflammation and osteoclast differentiation. British J Pharmacology. 2012;165(7):2140–51.CrossRef
23.
da Silva FN, et al. Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice. Pharmacol Res. 2017;122:35–45.CrossRef
24.
Michalovicz LT, et al. The β‑adrenergic receptor blocker and anti-inflammatory drug propranolol mitigates brain cytokine expression in a long-term model of Gulf War Illness. Proc Natl Sci Counc Repub China B. 2021;285:119962.
25.
Hwa YL, et al. Beta-blockers improve survival outcomes in patients with multiple myeloma: a retrospective evaluation. Am J Hematol. 2017;92(1):50–5.PubMedCrossRef
26.
Nair R, et al. β adrenergic signaling regulates hematopoietic stem and progenitor cell commitment and therapy sensitivity in multiple myeloma. Haematologica. 2022;107(9):2226–31.PubMedPubMedCentralCrossRef
27.
Liu Y, Yu X, Zhuang J. Epinephrine Stimulates Cell Proliferation and Induces Chemoresistance in Myeloma Cells through the β‑Adrenoreceptor in vitro. Acta Haematol. 2017;138(2):103–10.PubMedCrossRef
28.
Liu S, Costa M. The role of NUPR1 in response to stress and cancer development. Toxicol Appl Pharmacol. 2022;454:116244.PubMedCrossRef
29.
Yang EV, et al. VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine. Brain Behav Immun. 2008;22(3):318–23.ADSPubMedCrossRef
30.
Johannesdottir SA, et al. Use of β‑blockers and mortality following ovarian cancer diagnosis: a population-based cohort study. Bmc Cancer. 2013;13:85.PubMedPubMedCentralCrossRef
31.
Nilsson MB, Langley RR, Fidler IJ. Interleukin‑6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65(23):10794–800.PubMedPubMedCentralCrossRef
32.
Patel SA, et al. IL6 Mediates Suppression of T‑ and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC. Clin Cancer Res. 2023;29(7):1292–304.PubMedPubMedCentralCrossRef
33.
Men L, et al. IL-6/gp130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic β‑adrenergic stimulation. Free Radic Biol Med. 2023;.
34.
Zhang H, et al. The gp130/STAT3 signaling pathway mediates β‑adrenergic receptor-induced atrial natriuretic factor expression in cardiomyocytes. Febs J. 2008;275(14):3590–7.PubMedCrossRef
35.
Päth G. n., et al., Human breast adipocytes express interleukin‑6 (IL-6) and its receptor system: increased IL‑6 production by β‑adrenergic activation and effects of IL‑6 on adipocyte function. J Clin Endocrinol Metab. 2001;86(5):2281–8.PubMed
36.
Yang EV, et al. Norepinephrine upregulates VEGF, IL‑8, and IL‑6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23(2):267–75.MathSciNetPubMedCrossRef
37.
Bernabé DG, et al. Stress hormones increase cell proliferation and regulates interleukin‑6 secretion in human oral squamous cell carcinoma cells. Brain Behav Immun. 2011;25(3):574–83.PubMedCrossRef
38.
Men L, et al. IL-6/gp130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic β‑adrenergic stimulation. Free Radic Biol Med. 2023;205:163–74.PubMedCrossRef
39.
Xu L, et al. miR-451a targeting IL-6R activates JAK 2/STAT3 pathway, thus regulates proliferation and apoptosis of multiple myeloma cells. J Musculoskelet Neuronal Interact. 2022;22(2):251–60.MathSciNetPubMedPubMedCentral
40.
Liu Y, et al. IL‑6 Regulates the Chemosensitivity of Drug-Resistant Multiple Myeloma Cell Lines to Bortezomib through STAT3/Notch Signaling Pathway. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2022;30(5):1474–81.MathSciNetPubMed
41.
Juge-Morineau N, et al. The gp 130 family cytokines IL‑6, LIF and OSM but not IL-11 can reverse the anti-proliferative effect of dexamethasone on human myeloma cells. Br J Haematol. 1995;90(3):707–10.PubMedCrossRef
42.
Di Fonte R, et al. Cervical cancer benefits from trabectedin combination with the β‑blocker propranolol: in vitro and ex vivo evaluations in patient-derived organoids. Front Cell Dev Biol. 2023;11:1178316.PubMedPubMedCentralCrossRef
43.
Solernó LM, et al. Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy. Sci Rep. 2022;12(1):15058.ADSPubMedPubMedCentralCrossRef
44.
Yuan W, Wang X. Propranolol Participates in the Treatment of Infantile Hemangioma by Inhibiting HUVECs Proliferation, Migration, Invasion, and Tube Formation. Biomed Res Int. 2021;p:6636891.
45.
Lamy, S., et al., Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol, 2010. 53(5–6): p. 200–8.
46.
Seyedi S, et al. The Effects of Isoproterenol and Propranolol on Cytokine Profile Secretion by Cultured Tumor-infiltrating Lymphocytes Derived from Colorectal Cancer Patients. Cell J. 2012;13(4):281–9.PubMed
47.
Madden KS, Szpunar MJ, Brown EB. β‑Adrenergic receptors (β-AR) regulate VEGF and IL‑6 production by divergent pathways in high β‑AR-expressing breast cancer cell lines. Breast Cancer Res Treat. 2011;130:747–58.PubMedPubMedCentralCrossRef
48.
Shaashua L, et al. Perioperative COX‑2 and β‑Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial. Clin Cancer Res. 2017;23(16):4651–61.PubMedPubMedCentralCrossRef
49.
Valles SL, et al. Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism. J Transl Med. 2013;11:72.PubMedPubMedCentralCrossRef
50.
Chaudhary KR, et al. Effects of β‑Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. J Clin Med. 2019;8(5).
51.
Albiñana V, et al. Propranolol: A “Pick and Roll” Team Player in Benign Tumors and Cancer Therapies. J Clin Med. 2022;11(15).
52.
Kozanoglu I, et al. New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma. J Cancer Res Clin Oncol. 2013;139(2):327–35.PubMedCrossRef
53.
Maytalman E, et al. Adrenergic receptor behaviors of mesenchymal stem cells obtained from different tissue sources and the effect of the receptor blockade on differentiation. J Recept Signal Transduct Res. 2022;42(4):349–60.PubMedCrossRef
54.
Ma H, et al. Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma. Cancer Sci. 2019;110(3):950–61.PubMedPubMedCentralCrossRef
55.
Galm, O., et al., SOCS‑1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood, The Journal of the American Society of Hematology, 2003. 101(7): p. 2784–2788.
56.
Martínez-Baños D, et al. Global methylation and promoter-specific methylation of the P16, SOCS‑1, E‑cadherin, P73 and SHP‑1 genes and their expression in patients with multiple myeloma during active disease and remission. Exp Ther Med. 2017;13(5):2442–50.PubMedPubMedCentralCrossRef
57.
Amodio N, et al. miR-29b induces SOCS‑1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. Cell Cycle. 2013;12(23):3650–62.PubMedPubMedCentralCrossRef
58.
59.
Yamamoto M, et al. Suppressor of cytokine signaling‑1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells. Cancer Gene Ther. 2006;13(2):194–202.PubMedCrossRef
Metadaten
Titel
β-adrenergic modulation of IL-6/gp130 and SOCS-1 in multiple myeloma: therapeutic strategy for stress induced-inflammatory response
verfasst von
Raika Naiebi
Saeid Abroun, Ph. D.
Amir Atashi
Leila Shafiee
Mohammadarian Akbari
Mohammad Hasan Maleki
Morvarid Siri, M. Sc.
Publikationsdatum
09.02.2024
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-024-00962-0

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